SK113897A3 - Phenylsubstituted alkenylcarboxylic acid guanidides, method of preparation, their use as a drug or a diagnostic agent and a drug containing the same - Google Patents

Abstract

Diphenyl-substituted alkenyl-carboxylic acid guanidides of g eneral formula (I), wherein T is a group of general formula T, RA , RB, RC and RD are hydrogen, halogen, cyano group, optionally su bstituted hydroxy group, (C1-C4)-alkyl, fluoro-substituted alkyl, (C3-C8)-cycloalkyl or substituted amino group, x is 0, 1 or 2, y is 0, 1 or 2, RE and RF are hydrogen, halogen, cyano group, subs tituted hydroxy group, (C1-C8)-alkyl, fluoro-substituted alkyl, ( C3-C8)-cycloalkyl or (C1-C9)-heteroaryl, R1, R2, R3, R4 and R5 ha ve the meaning as T, or are hydrogen, optionally fluoro-substitut ed alkyl or alkoxyl, halogen, cyano group, or defined organic res idue, or R1 and R2, or R2 and R3 mean together optionally substit uted group -CH-CH=CH-CH-, whilst the residue T is present in the molecule at least twice, most three times, as well as their pharm aceutical acceptable salts, are effective inhibitors of the cell exchange system Na+/H+. Preparation method for these compounds, m edicaments containing them and their use.

Description

Described are guanidides of a phenyl-substituted alkenylcarboxylic acid, a process for their preparation, their use as a medicament or a diagnostic agent, as well as a medicament containing them.

BACKGROUND OF THE INVENTION

The most important examples of acylguanidines are the pyrazinecarboxylic acid and benzoic acid guanidides V and VI

(V) (VI) refer to as amilorides. The amiloride itself (R and R 'in each case represents a hydrogen atom) is used in therapy as a potassium-sparing diuretic. A number of are described in the literature

Amiloride: R and R 'are each hydrogen, Dimethylamiloride: R and R' are each methyl,

Ethylisopropylamiloride: R is CH (CH ₃ ) ₂ / R 'is C ₂ H ₅

Compounds of formula V are commonly known in the literature to other amiloride-based compounds such as dimethylamiloride or ethylisopropylamiloride.

Investigations are known which point to the antiarrhythmic properties of amiloride (Circulation 79, 1257-1263 (1989)). However, wider use as an antiarrhythmic agent is hampered by the fact that this effect is only weak and is accompanied by blood pressure lowering and saluretic effects, which are undesirable as side effects in the treatment of cardiac rhythm disorders.

References to the antiarrhythmic properties of amiloride have also been obtained in experiments on isolated animal hearts (Eur. Heart J. 9 (suppl. 1), 167 (1988) (book of abstracts)). Thus, for example, it has been found in rat hearts that artificially induced ventricular oscillations can be completely suppressed by amiloride. Even more potent than amiloride in this model was the above-mentioned amiloride derivative, ethylisopropylamiloride.

Compounds of formula VI are selective inhibitors of the ubiquitous sodium-proton exchange system (subtype 1, NHE-1; Na ⁺ / H ⁺ -exchanger subtype 1). Representatives of these compounds known from the literature are compounds HOE 694 and HOE 642, which disclose antiarrhythmic and cardioprotective effects under ischemic conditions a) Scholz W., Albius U., Linz W., Martorana P., Lang HJ, Scholkens BA: Effects of Na ⁺ / H ⁺ exchange inhibitors in cardiac ischemia, J. Mol. Cell. Cardiol. 24: 731-739 (1992); b) Scholz W., Albus U .: Na ⁺ / H ⁺ exchange and its inhibition in cardiac ischemia and reperfusion, Basic Res. Cardiol. 88: 443-455 (1993); (c) Scholz W., Albus U., Counillon L., Gôgelein H., Lang HJ, Linz W., Weichert A., Scholkens BA: Protective effects of HOE 642, and selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischemia and reperfusion, Cardiovasc. Res. 29, 260-268 (1995); (d) Bugge E., Ytrehus K .: Inhibition of Sodium Hydrogen Exchange in Infarct Size in the Isolated Rat Heart. Protective additive to ischemic preconditioning, Cardiovasc. Res. 29, 269-274 (1995).

Furthermore, guanidides are known from the literature as NHE inhibitors (Na ⁺ / H 'exchange)

3-phenyl- and 3-thiophenylpropenoic acid of the general formula VII (US 2,734

904, WO 84/00875, DE-OS 44 21

536.3)

(VII) wherein R ¹ represents a phenyl or thiophenyl group;

However, no bisguanidine compounds of formula I below are described or evident in these documents.

SUMMARY OF THE INVENTION

The invention relates to the guanidides of the phenyl-substituted alkenylcarboxylic acid of the formula I

in which

T represents a group of the general formula

R ^a is H, F, Cl, Br,, CN, OH, OR ^6, alkyl of 1 to 4 carbon atoms, 0 _{r (CH2) a} C _b F _2b + i, cycloalkyl having 3 to 8 carbon atoms or NR ⁷ R ^8, r is 0 or 1,

and 0, 1, 2, 3, or 4 b is 1, 2, 3 or 4 R ⁶ represents an alkyl group with 1 to 4 carbon alkyl, perfluoroalkyl group with 1 to 4 carbon carbon an alkenyl group having 3 to 6 carbon alkyl, cycloalkyl having from 3 to 3 carbon atoms; 8 atoms alkyl, phenyl

or a benzyl group, wherein the phenyl ring is unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁹ R ¹⁰ groups, R ⁹ and R ¹⁰ are each hydrogen , alkyl of 1 to 4 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms; R ⁷ and R ⁸ independently of one another each as defined for the symbol R ^6, or the radicals R ⁷ and R ³ together are 4 or 5 methylene groups of which one CH ₂ group can be replaced by an oxygen, sulfur, NH, NCH ₃ or N-benzyl group, R ^B , R ^C and R 0 are each independently as defined for R ^A , x is 0, 1, or 2, y is 0, 1, or 2,

R ^f is H, F, Cl, Br, I, CN, OR ^12, alkyl of 1 to 8 carbon atoms, O _{p (CH2) f} C _g F _{2G +} i, cycloalkyl having 3 to 8 carbon p is 0 or 1, f is 0, 1, 2, 3 or 4, g is 1, 2, 3, 4, 5, 6, 7 or 8,

R ¹² is C 1 -C 8 alkyl, C 1 -C 4 perfluoroalkyl, C 3 -C 8 alkenyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, the phenyl ring being unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ¹³ R ¹⁴ groups, R ¹³ and R ¹⁴ are each hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 perfluoroalkyl,

R ^e is independently as defined for R ^F ,

R ¹ is independently as defined for the symbol T, or

R ¹ represents H, -OkCmH2m + i, -On (CH2) i-pCqF2q, F, Cl, Br, I, CN, - (C = O) -N = C (NH 2) 2, -S0rR ^17, -SOr2NR ³¹ R ^32, O _{and (CH2)} vC ₆ H _5, -O _u2 heteroaryl of 1-9 carbon atoms or -Su ₂ -heteroaryl containing 1 to 9 carbon atoms, k is 0 or 1, m is 0, 1, 2, 3, 4, 5, 6, 7 or 8,

n my 0 or 1 P my 0, 1, 2, 3, or 4 q my value 1, 2, 3, 4, 5, 6, 7 r my 0, 1, or 2 r2 my 0, 1, or 2

the symbols R ³¹ and R ³² independently of one another are hydrogen, alkyl having 1 to 8 carbon atoms or perfluoroalkyl of 1 to 8 carbon atoms, or the radicals R ³¹ and R ³² together are 4 or 5 methylene groups, of which the be one CH ₂ replaced by an oxygen, sulfur, NH, N-CH ₃ or N-benzyl group,

R ¹⁷ represents an alkyl group having 1 to 8 carbon atoms,

at 0 or 1 u2 is 0 or 1 in 0, 1, 2, 3, or 4 wherein the phenyl ring is unsubstituted or substituted

one to three substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, - (CH ₂ ) _W NR ²¹ R ²² , NR ¹⁸ R ¹⁹ and heteroaryl groups of 1 to 9 carbon atoms, R ¹⁸ , R ¹⁹ , R ²¹ and R ^{22 are} each independently of each other

an alkyl group having from 1 to 5 carbon atoms; perfluoroalkyl having 1 to 5 carbon atoms; 4 carbon atoms 4 carbon atoms, or w is 1, 2, 3 or 4 wherein the heteroaryl heterocycle groups of 1 to 9 carbon

carbon is unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl and methoxy, R ² , R ³ , R ⁴ and R ⁵ are each independently as defined for R ¹ , or R ( ¹⁾ and R ( ²⁾ or R ( ²⁾ and R ( ³⁾ together are --CH - CH.dbd.CH - CH-- which is unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group - (CH ₂ ) _{M 2} NR ²⁴ R ²⁵ and NR ²⁶ R ²⁷ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁷ are each hydrogen, C 1 -C 4 alkyl or perfluoroalkyl; And w 2 has a value of 1, 2, 3 or 4, wherein the T moiety is present in the molecule at least two, but at most three, as well as their pharmaceutically acceptable salts.

Preferred are compounds of formula I in which

T represents a group of the general formula

R ^a is H, F, Cl, CN, OH, OR ^6, alkyl of 1 to 4 carbon atoms, 0 _{r (CH2) a} C _b F _{2b +} i, cycloalkyl having 3 to 8 carbon carbon or NR ⁷ R ³ , r is 0 or 1, and is 0, 1, or 2, b is 1, 2, 3, or 4

R ⁶ is C 1 -C 4 alkyl, C 1 -C 4 perfluoroalkyl, phenyl or benzyl, the phenyl ring being unsubstituted or substituted by one to three substituents selected from fluoro, chloro, trifluoromethyl , methyl, methoxy and NR ⁹ R ¹⁰ , R ⁹ and R ¹⁰ are each independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl, R ⁷ and R ⁸ They are each independently of one another as defined for the symbol R ^6, or the radicals R ⁷ and R ⁸ are together or 5 methylene groups, of which one _CH2 group can be replaced by O, S, NH, _N-CH3 or N benzyl, R ^s , R ^c and R ^D are each independently as defined for R ^A , x is 0 or 1, y is 0 but bo 1,

R ^F represents a hydrogen, fluorine or chlorine atom, a cyano group, an OR ¹² group, a C 1 -C 4 alkyl group, a 0 _p (CH ₂ ) _f CgF _{2 g +} 1 group, a C 3 -C 8 cycloalkyl group or a 1-heteroaryl group up to 9 carbon atoms, p is 0 or 1, f is 0, 1 or 2 g is 1, 2, 3 or 4,

R ¹² is C 1 -C 4 alkyl, C 1 -C 4 perfluoroalkyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, wherein the phenyl ring is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkyl, phenyl or benzyl. consisting of fluorine, chlorine, trifluoromethyl, methyl, methyl, methoxy and NR ¹³ R ^14; R ¹³ and R ¹⁴ independently of one another, are hydrogen, methyl or trifluoromethyl,

R ¹¹ is independently as defined for R ^f ,

R ¹ is independently as defined for the symbol T, or

R ¹ represents H, -OkCmH2mti, -OnCqF2qti, F, Cl, Br, I, CN, (C = 0) -N = C (NH 2) 2, -SOR ^17, -SOr2NR ³¹ R ^32, - 0 _and (CH ₂₎ C ₆ H ₅ group,

_{U2-O-heteroaryl} having 1 to 9 carbon atoms, or -S-heteroaryl _U2

s 1 k up to 9 carbon atoms, 0 or 1, m is 0, 1, 2, 3 or 4 n is 0 or 1 q is 1, 2, 3 or 4 r is 2 r2 0, 1, or 2 the symbols R ³¹ and R ³² independently of one another denote a free-

dika, (C 1 -C 4) alkyl or (C 1 -C 4) perfluoroalkyl, or R ³¹ and R ¹² together represent 4 or 5 methylene groups, of which one CH ₂ may be replaced by an oxygen, sulfur, NH, N-CH ₃ or N-benzyl,

R ¹⁷ is C 1 -C 4 alkyl, u is 0 or 1, u 2 is 0 or 1 v is 0, 1 or 2 wherein the phenyl ring is unsubstituted or substituted with one to three substituents selected from fluoro , chloro, trifluoromethyl, methyl, methoxy, - (CH _{2) w} NR ²¹ R ^22, NR ^s R ^19, and heteroaryl of 1-9 carbon atoms; R ^18, R ^19, R ²¹ and R ²² in each case represent a C1-C4 alkyl group or a C1-C4 perfluoroalkyl group, w having a value of 1, 2, 3 or 4 wherein the heterocycle of the C1-C9 heteroaryl group is unsubstituted or substituted by one to three substituents selected from a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group and a methoxy group, R ² , R ³ , R ⁴ and R ⁵ independently of each other have the meanings of def R ^{@ 1} or R @ ² or R @ ² and R @ ³ together represent --CH - CH.dbd.CH - CH-- which is unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl - (CH ₂ ) _{w 2} NR ²⁴ R ²⁵ and NR ²⁶ R ²⁷ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁷ are each hydrogen, methyl or trifluoromethyl, and w 2 has a value of 1, 2, 3 or 4, but the T moiety is present only twice in the molecule, as well as their pharmaceutically acceptable salts.

Particularly preferred are compounds of formula I wherein T is a group of formula

x is 0, y is 0,

R ^F is H, F, Cl, CN, OR ^12, alkyl of 1 to 4 carbon atoms, O _p C _g F _{2G +} i, cycloalkyl having 3 to 8 carbon atoms or a heteroaryl group having 1-9 carbon carbon, p is 0 or 1, g is 1, 2, 3 or 4,

R ¹² is C 1 -C 4 alkyl, trifluoromethyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, the phenyl ring being in each case unsubstituted or substituted by one to three substituents selected from fluorine, chloro, trifluoromethyl, methyl, methoxy and NR ¹³ R ^14; R ¹³ and R ¹⁴ are hydrogen, methyl or trifluoromethyl,

R ^E is independently as defined for R ^F ,

R ¹ is independently as defined for the symbol T, or

R ¹ represents H, -OkCmH2m + i, "OnCqF2q4.i, fluorine, chlorine, cyano, - (C = O) -N = C (NH 2) 2, -SO2CH3, -SO 2 NR ³¹ R ^32, - ou (CH ₂₎ C ₆ h _5, group -Ou2 ^- heteroaryl containing 1 to 9 carbon atoms or -S _U2 ^_ heteroaryl having 1 to 9 carbon atoms, k is 0 or 1, m is 0, 1, 2, 3 or 4 n is 0 or 1 q is 1, 2, 3 or 4 R ³¹ and R ³² are each independently hydrogen or C 1 -C 4 alkyl or R ³¹ and R ^{32 32} together are 4 or 5 methylene groups, of which one may be a CH ₂ replaced by O, S, NH, _N-CH3 or N-benzyl;

at my value 0 or 1 u2 my value 0 or 1 in my value 0 or 1

wherein the phenyl ring is unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, - (CH ₂ ) _W NR ²¹ R ²² and NR ¹⁸ R ¹⁹ , R ¹⁸ , R ¹⁹ , R ²¹ and R ^{22 are} each independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl, w has a value of 1, 2, 3 or 4 wherein the heterocycle of the heteroaryl group with 1 up to 9 carbon atoms are unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group and methoxy group, R ² , R ³ , R ⁴ and R ⁵ are each independently as defined for R ^{@ 1} or R ^{@ 1} and R ^{@ 2} or R @ ² and R @ ³ together together represent --CH - CH.dbd.CH - CH-- which is unsubstituted or substituted one to three substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, - (CH ₂ ) _{W 2} NR ²⁴ R ²⁵ and NR ²⁶ R ²⁷ , R ²⁴ , R ²⁵ , R ²⁶ and R ^{26 Each} independently represents a hydrogen atom, a (C1-C4) alkyl group or a (C1-C4) perfluoroalkyl group and w2 is 1, 2, 3 or 4, but the residue T in the molecule is present only twice as and pharmaceutically acceptable salts thereof.

The following compounds are particularly preferred:

1,2-bis- [3- (E-2-methyl-propene-guanidide)] benzene dihydrochloride,

1,3-bis- [3- (E-2-methyl-propene-guanidide)] benzene dihydrochloride,

1,4-bis- [3- (E-2-methyl-propene-guanidide)] benzene dihydrochloride,

2,3-bis- [3- (E-2-methyl-propene-guanidide)] naphthalene dihydrochloride,

1,2-bis- [3- (Ζ-2-fluoro-propene-guanidide)] benzene dihydrochloride,

1- [3- (Ζ-2-fluoro-propene-guanidide)] -2- [3- (ε-2-methyl-propene-guanidide)] benzene dihydrochloride,

1,3-bis- [3- (Ζ-2-fluoro-propene-guanidide)] benzene dihydrochloride,

3- (4-Chloro-3-guanidinocarbonyl-5-phenyl) phenyl-2-methylpropenuanide

1,3-bis- [3- (E-2-methyl-propene-guanidide)] - 2-methoxy-5-methyl-benzene hydrochloride

1,2-Bis- [3- (E-2-methyl-propene-guanidide)] -4-methylbenzene dihydrochloride

1,2-Bis- [3- (E-2-methyl-propene-guanidide)] - 4,5-dichlorobenzene dihydrochloride

1,3-bis- [3- (E-propene guanidide)] benzene dihydrochloride

1,2-Bis- [3- (E-2-methyl-propene-guanidide)] -4-bromobenzene dihydrochloride

1,2-bis- [3- (E-2-methylpropenuanidide)] -4- (4-methoxyphenoxy) benzene dihydrochloride

1,2-bis- [3- (E-2-methyl-propene-guanidide)] -4- (4-methylphenoxy) -benzene dihydrochloride

1,3-bis- [3- (E-2-methyl-propene-guanidide)] -5-methoxybenzene hydrochloride

1,3-bis- [3- (E-2-methyl-propene-guanidide)] -5-tert-butyl-benzene hydrochloride

1,4-bis- [3- (E-2-methyl-propene-guanidide)] -2,5-dichloro-benzenedihydrochloride

1,2-bis- [3- (E-2-methyl-propene-guanidide)] - 4- (phenoxy) benzene dihydrochloride

1,2-bis- [3- (E-2-methyl-propene-guanidide)] 4- (methoxy) benzene dihydrochloride

1,2-bis- [3- (E-2-methyl-propene-guanidide)] - 4- (ethoxy) benzene dihydrochloride and

1,2-Bis- [3- (E-2-methyl-propene-guanidide)] - 4- (3-pyridyloxy) -benzene dihydrochloride.

By propenguanidide is meant propanic acid guanidide.

When the compounds of formula I contain one or more centers of asymmetry, they may exist in both the S- and R-configuration. The compounds of the invention may exist as optical isomers, diastereomers, racemates, or mixtures thereof.

The double bond arrangement of the compounds of formula I may be in both the E- and Z-configuration. These compounds may exist as isomers at the double bond in the mixture.

Said alkyl and perfluoroalkyl radicals may have both straight and branched chains.

The term C 1 -C 9 heteroaryl means, in particular, radicals derived from phenyl or naphthyl, in which one or more CH groups are replaced by a nitrogen atom and / or in which at least two adjacent CH groups are replaced by a sulfur atom, NH or atom of oxygen to form a five-membered aromatic ring. Furthermore, they can also be one or both of the bicyclic radicals, nitrogen atoms).

Heteroaryl groups include sites (such as, for example, indolizinylthienyl, azolyl, lyl, midinyl, pyrrolyl, tetrazolyl, isothiazolyl, pyridazinyl, imidazolyl, oxazolyl, pyridyl, indolyl, furanyl, pyrazolyl, pyrazolinyl, isoxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, isoxazolyl) , phthalazinyl, quinoxalinyl, quinazolinyl and cinolinyl.

invention take on concerns way preparation compound of of formula I, which is characterized by getting compound of of formula II R ⁴ RF r9 L JL l · (II) R ^{1 S} R ^c n _r a _r e-- y x

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^A , R ^B , R ^c , R ^c , R ^c , R ^f , x and y have the meanings given above and L is a nucleophilic substitution readily displaceable leaving group , is reacted with guanidine.

The activated acid derivatives of the formula II in which L represents an alkoxy group, in particular a methoxy or phenoxy group, a phenylthio group, a methylthio group, a 2-pyridylthio group or a nitrogen heterocyclic radical, especially a 1-imidazolyl group, are obtained in a known manner from the carboxylic acid starting compounds. of formula II, where L is a chlorine atom), which in turn can also be prepared in a manner known per se from the starting carboxylic acids (compounds of formula II, wherein L is a hydroxyl group), for example by reaction with thionyl chloride.

In addition to the carboxylic acid chlorides of the formula II (in which L is a chlorine atom), other activated acid derivatives of the formula II, such as, for example, the methyl ester, can also be prepared directly from known alkenyl acid derivatives (compounds of formula II in which L represents a hydroxyl group). of formula II, wherein L is methoxy, by reaction with hydrogen chloride gas in methanol, an imidazolide of formula II, wherein L is

1-imidazolyl group, by reaction with carbonyldiimidazole (Staab:

Angew. Chem., Int. Ed.

Engl.

1

351-367 (1962)) or mixed anhydrides of the general formula

II by reaction with ethyl chloroformate or tosyl chloride in the presence of triethylamine in an inert solvent. Activation of alkenoic acids can also be accomplished with dicyclohexylcarbodiimide (DCC) or O [(cyano (ethoxycarbonyl) methylene) amino] -1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) (Proceedings of the 21st European Peptide Symposium, Peptides 1990, E. Peptides, 1990). D. Andreu Eds., Escom, Leiden 1991). A variety of suitable methods for preparing activated carboxyl derivatives

II is the work described in the literature, J. March: Advanced Organic Acids of the general formula which is listed

Chemistry, 3rd cited in

Ed., John

Wiley & Sons, 1985, page 350.

Reaction of the activated derivative by the general method of Formula II with guanidine in a protic or aprotic solvent. In the reaction of the carboxylic acid, the acid is carried out with an already known organic acid (a compound of the formula methoxy) with guanidine and isopropanol or tetrahydrofuran at the boiling point of these solvents.

polar but inert alkenyl methyl ester

Preferably, the reaction of the compounds of formula II with salt-free guanidine is preferably carried out in aprotic inert solvents such as tetrahydrofuran, dimethoxyethane or dioxane. However, water in the presence of a base such as sodium hydroxide can also be used as a solvent in the reaction of the compound of formula II with guanidine.

If L represents a chlorine atom, it is preferably carried out by adding an acid-binding agent, for example in the form of excess guanidine to bind the hydrohalic acid.

Part of the starting alkenylic acid derivatives of formula (II) is known and described in the literature. The unknown compounds of formula II can be prepared by methods known in the literature. The alkenyl acids obtained are converted by one of the variants described above into the compounds of the formula I according to the invention.

The introduction of some substituents is carried out by methods known in the literature by means of palladium-mediated cross-coupling of aryl halides or aryltrifluoromethanesulfonates, for example with organostannates, organic boron acids or organoborates or organic copper or zinc compounds.

The alkenylguanidines of formula I are generally weak bases and can bind acids to form salts. Suitable acid addition compounds are salts of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates and p-toluenesulfonates.

The compounds of formula I are substituted acylguanidines.

It is surprising that the compounds of formula I according to the invention inhibit the sodium exchange system with protons of subtype 3. The prior art NHE inhibitors (Na ⁺ / H * -exchanger) are hardly effective on this subtype.

The compounds of formula I lower blood pressure and are therefore useful as medicaments for the treatment of primary and secondary hypertonia. Due to their salidiuretic action, they are suitable as diuretics.

In addition, the compounds of the invention, alone or in combination with NH subtype inhibitors specific for another subtype, act anti-ischemic. They protect organs acutely or chronically under-supplied with oxygen, by reducing or preventing ischemic-induced damage, and are therefore useful as medicaments in, for example, thromboses, vascular spasms, atherosclerosis or surgical procedures (e.g., organ kidney and liver transplants) be used both to protect organs in the donor from and during organ harvesting, and to protect organs taken, for example, from handling or storing such organs in physiological fluids, and also when transferred to a recipient organism) or chronic or acute failure impairment.

Because of their protective action against ischemic-induced disorders, these compounds are also useful as medicaments for the treatment of ischemia of the nervous system, in particular of the central nervous system, for example for treating stroke (apoplexy) or cerebral edema. In addition, the compounds of the formula I according to the invention are also suitable for the treatment of various forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

The compounds of the invention further induce improved respiratory stimulation and can therefore be used to treat respiratory disorders in the following clinical conditions and diseases: impaired central respiratory stimulation (e.g., central sleep apnea, sudden death of children, postoperative hypoxia), muscular respiratory disorders, respiratory disorders long-term artificial respiration, respiratory disorders in adaptation to alpine environment, obstructive and mixed forms of sleep apnea, acute and chronic lung diseases associated with hypoxia and hypercapnia.

The combination of an NHE inhibitor and a carbonic anhydrase inhibitor (e.g. acetazolamide), which causes metabolic acidosis and thus increases respiratory activity, has proven to be a suitable combination with potentiated action and a reduced amount of active ingredient used.

In addition, the compounds of the formula I according to the invention are characterized by a potent inhibitory action on cell proliferation, for example on vascular smooth muscle cells.

Therefore, the compounds of general effective therapeutics in diseases, in primary cell proliferation come and can therefore be used as antido considerations as a secondary cause, atherosclerotics, means of complications, against cancer against late diseases, against diabetic fibrotic diseases such as is lung fibrosis, liver fibrosis or kidney fibrosis, against endothelial dysfunction and against hypertrophies and hyperplasia of organs, especially prostate hyperplasia or prostate hypertrophy. In addition, these compounds cause cholesterol lowering and are therefore useful as medicaments for the prevention and treatment of atherosclerosis.

The compounds of the present invention are potent inhibitors of the Na ⁺ / H ^T cell subtype 1 and 3 cell exchange (antiporter) system, which is elevated in many diseases (essential hypertonia, atherosclerosis, diabetes, etc.) even in cells readily accessible for measurement such as Thus, the compounds of the invention are useful as excellent and simple scientific tools, for example, in their use as diagnostic agents for the determination and differentiation of certain forms of hypertonia, but also arteriosclerosis, diabetes, proliferative diseases, etc. compounds of formula I suitable for preventive therapy to prevent the development of high blood pressure, such as essential hypertonia.

In addition, the compounds of formula I have been found to favorably affect serum lipoproteins. It is generally accepted that excessively high levels of blood fat, the so-called hyperlipoproteinaemia, are an important risk factor for arteriosclerotic vascular changes, particularly coronary heart disease. Thus, reducing the elevated serum lipoprotein levels is of particular importance for the prophylaxis and regression of atherosclerotic changes. In addition to lowering total serum cholesterol, it is of particular importance to reduce the proportion of particular atherogenic lipid fractions of this total cholesterol, particularly low density lipoproteins (LDLs) and very low density lipoproteins (VLDLs), since these lipid fractions they represent an atherogenic risk factor. On the other hand, high density lipoproteins are attributed a protective function against coronary heart disease. Accordingly, hypolipidemics should be capable of lowering not only total cholesterol, but especially the level of VLDL- and LDL-fractions of serum cholesterol. It has now been found that compounds of formula I exhibit valuable therapeutically useful properties as a result of affecting serum lipid levels. Thus, these compounds significantly reduce elevated serum LDL and VLDL concentrations, which are observed, for example, as a result of increased dietary intake of a cholesterol-rich and lipid-rich diet or pathological changes in metabolism, such as genetic-related hyperlipidemia. Thus, they can be used for the prophylaxis and regression of atherosclerotic changes, which eliminate the causal risk factor. This includes not only primary hyperlipidemia, but also certain secondary hyperlipidemia, which occurs, for example, in diabetes. In addition, the compounds of formula I result in a marked reduction in infarcts induced by metabolic anomalies, and in particular in a substantial reduction in the infarct induced range and severity. Further, the compounds of formula I provide effective protection against endothelial damage caused by metabolic anomalies. As a result of this vascular protection against endothelial dysfunction syndrome, the compounds of formula I are effective drugs for the prevention and treatment of coronary artery spasms, atherogenesis and arteriosclerosis, left ventricular hypertrophy and dilated cardiomyopathy, and thrombotic diseases.

The compounds are therefore preferably used for the preparation of a medicament for the treatment of hypercholesterolemia, for the preparation of a medicament for the prevention of atherogenesis, for the preparation of a medicament for the prevention and treatment of atherosclerosis, are induced by elevated drug levels for the prevention and treatment of dysfunction, for the preparation of the drug for induced hypertonia, for the treatment of atherosclerosis prevention and for the preparation of the induced and for the treatment of the drug for atherosclerosis for prevention and thrombosis; reperfusion injury, prevention and treatment of hypercholesterolaemia and endothelial dysfunction-induced cardiac myopathies, for the preparation of a medicament for hypercholesterolaemia and endothelial convulsions (spasms) of coronary vessels and induced hypertrophy to and cardioa, and the treatment of a medicament for the prevention of myocardial infarction dysfunction or diseases of the above induced in combination with agents lowering preferably angiotensin receptor converting enzyme inhibitors.

potentiated action and reduced amount of substance proves to be a combination of an NHE I inhibitor with a blood pressure antagonist, angiotensin

As a suitable combination (ACE) with an effective formula of HMG-CoA reductase inhibitor used, a fat level (e.g., in blood, preferably lovastatin, or has hypolipidemic pravastatin therefrom), the second action thereby enhancing the hypolipidemic properties of the inhibitor

NHE of formula I.

The invention also relates to the administration of sodium exchange proton exchange inhibitors of the formula I as a novel medicament for reducing elevated blood fat levels, as well as combinations of sodium exchange proton exchange inhibitors with drugs that lower blood pressure and / or have a hypolipidemic effect.

Drugs containing a compound of the formula I can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred mode of administration being dependent on the current clinical manifestations of the disease. The compounds of the formula I can be used alone or together with galenic auxiliaries, both in veterinary and in human medicine.

The person skilled in the art will recognize, based on his / her expert knowledge, which excipients are suitable for the desired drug formulation. In addition to solvents, gelling agents, suppository bases, tablet excipients and other active ingredient carriers, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorants, preservatives, solubilizers or colorants can be used.

For oral use, the active compounds are admixed with excipients suitable for such inert diluents, suitable application and aqueous capsules, such as carriers, stabilizers, or formulated, and formulated, such as tablets, dragees, alcoholic or oily solutions, by conventional means.

Magnesium carbonate, for example, potassium arabate, gum, magnesium, milk sugar, glucose or starches, in particular corn starch, may be used as inert carriers.

In this case, the preparation can be carried out in the form of a dry wet granulate. Suitable oily excipients are, for example, vegetable oils or, as solvents, animal oils such as sunflower oil or fish oil.

For subcutaneous or intravenous administration, the active compounds, if desired together with substances customary for this purpose, such as solubilizers, emulsifiers or other excipients, are formulated as a solution, suspension or emulsion. Suitable solvents are, for example, water, physiological sodium chloride solution or alcohols, for example ethanol, propanol, glycerol, and also sugar solutions, such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.

Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, in particular ethanol or water, or in a mixture of such solvents.

If desired, the formulation may also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers as well as a propellant. Such a preparation usually contains the active compound in a concentration of from about 0.1 to 10, in particular from about 0.3 to 3% by weight.

The dosage of the active compound to be administered and the frequency of administration depend on the potency and duration of action of the compounds used and, moreover, on the type and severity of the disease to be treated and on the sex, age, weight and individual response of the mammal to be treated.

On average, a daily dose of a compound of Formula I is at least about 75 kg in a patient

0.001 mg / kg, in particular 0.01 mg / kg and not more than 10 mg / kg, in particular 1 mg / kg of body weight. In the event of an acute outbreak of the disease, even higher and, in particular, more frequent doses may be necessary, for example up to 4 sub-doses per day. In particular, for intravenous administration, for example in infarct patients in an intensive care unit, doses of up to 200 mg per day may be necessary.

DETAILED DESCRIPTION OF THE INVENTION

General process for the preparation of alkenyl carboxylic acid guanidides of the formula I:

Variant 1Ά: from alkenylcarboxylic acids (compounds of formula II in which L is a hydroxyl group)

1.0 equivalent of the carboxylic acid derivative of the formula II is dissolved or suspended in anhydrous tetrahydrofuran (5 ml / mmol) and 1.1 equivalents of carbonyldiimidazole are added. The mixture is stirred at room temperature for two hours and then 5.0 equivalents of guanidine are added to the reaction solution. The mixture is stirred overnight, then tetrahydrofuran is distilled off under reduced pressure on a rotary evaporator, water is added, the pH is adjusted to 6-7 with 2N hydrochloric acid and the corresponding guanidide (compound of formula I) is filtered off. The carboxylic acid guanidides thus obtained can be converted to the corresponding salts by treatment with aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically acceptable acids.

Variant 1B: from alkyl esters of alkenyl carboxylic acids (compounds of formula II wherein L is O-alkyl)

1.0 equivalents of carboxylic acid alkyl ester of formula II and 5.0 equivalents of guanidine (free base) are dissolved in isopropanol or suspended in tetrahydrofuran and the resulting solution or suspension is heated to reflux until reaction is complete (reaction control) is carried out by thin layer chromatography), a typical reaction time being 2 to 5 hours. The solvent was distilled off under reduced pressure on a rotary evaporator, the residue was dissolved in ethyl acetate and washed three times with sodium bicarbonate solution. It is dried over sodium sulphate, the solvent is distilled off in vacuo and the residue is chromatographed on silica gel using a suitable eluent, for example a 5: 1 mixture of ethyl acetate and methanol (salt formation as in variant A).

Example 1

1,2-Bis- [3- (E-2-methyl-propene-guanidide) Ibenzene dihydrochloride

1a) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

Of 1,2-phthalaldehyde. After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. Benzene-1,2-di [3- (E-2-methylpropenoic acid) diethyl ester] was isolated as a colorless oil. Mass spectrometry (desorption chemical ionization, DCI): 303 (Μ + Γ) 1b) The ester from step 1a) was saponified according to a standard procedure using sodium hydroxide in methanol. Benzene-1,2-di [3- (E-2-methylpropenoic acid)] was isolated as a colorless solid, m.p. > 187 ° C.

Mass spectrometry (DCI): 246 (M ⁺ ) 1c) The dicarboxylic acid of step 1b) was converted to diguanidide dihydrochloride according to variant 1A. The product is a colorless solid with a melting point above 200 ° C.

Mass spectrometry (DCI: 329 (M + 1) < ⁺ >)

Example 2

1,3-bis- [3- (E-2-methyl-propene-guanidide)] benzene dihydrochloride

2a) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

Of 1,3-isophthalaldehyde. After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. Benzene-1,3-di [3- (E-2-methylpropenoic acid) diethyl ester] was isolated as a colorless oil. Mass spectrometry (DCI): 303 (M + 1) < ^{+ >}

2b) The ester from step 2a) is saponified by a standard procedure using sodium hydroxide in methanol. Benzene-1,3-di [3- (E-2-methylpropenoic acid)] was isolated as a colorless solid, m.p. > 190 ° C.

Mass Spectrometry (DCI): 247 (M + 1) < ^{+ >}

2c) The dicarboxylic acid of step. 2b) is converted to diguanidide dihydride chloride according to variant 1A. The product is a colorless solid with a melting point above 175 ° C.

Mass Spectrometry (DCI): 329 (M + 1) < ^{+ >}

Example 3

1,4-bis- [3- (E-2-methyl-propene-guanidide)] benzene dihydrochloride

NH, O

O NH ₂

3a) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

1,4-terephthalaldehyde. After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. Benzene-1,4-di [3- (E-2-methylpropenoic acid) diethyl ester is isolated as a colorless solid, m.p. 41 ° C.

Mass spectrometry (DCI): 303 (M + 1) < ^{+ >}

3b) The ester from step 3a) is saponified by a standard procedure using sodium hydroxide in methanol. Benzene-1,4-di [3- (ε-2-methylpropenoic acid)] is isolated as a colorless solid with a melting point above 190 ° C.

Mass Spectrometry (DCI): 247 (M + 1) < + >

3c) The dicarboxylic acid of step 3b) is converted according to variant 1A to diguanidide dihydrochloride. The product is a yellow solid with a melting point above 255 ° C.

Mass Spectrometry (DCI): 329 (M + 1) < ^{+ >}

Example 4

2,3-bis- [3- (E-2-methyl-propene-guanidide)] naphthalene dihydrochloride

4a) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

2,3-naphthalenedicarboxaldehyde. After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. The naphthalene-2,3-di [3- (E-2-methylpropenoic acid) diethyl ester was isolated as a colorless oil. Mass Spectrometry (DCI): 353 (M + 1) < ^{+ >}

4b) The ester from step 4a) is saponified by a standard procedure using sodium hydroxide in methanol. Naphthalene-2,3-di- [3- (E-2-methylpropenoic acid)] is isolated as a colorless solid, m.p. > 210 ° C.

Mass Spectrometry (DCI): 295 (M-H) ”

4c) The dicarboxylic acid of step 4b) is converted to diguanidide dihydrochloride according to variant 1A. The product is a colorless solid with a melting point above 200 ° C.

Mass Spectrometry (DCI): 379 (M + 1) < ^{+ >}

Example 5

1,2-bis- [3- (Ζ-2-fluoro-propene-guanidide)] benzene dihydrochloride

5a) Using a procedure known from the literature (Cousseau et al .: Tetrahedron Lett. 34, 6903 (1993)), starting from 1,2-phthalialdehyde, benzene-1,2-di- [3- (Z-2-fluoropropene) diethyl ester is prepared. acid), which is purified and isolated on silica gel, eluting with a mixture of ethyl acetate and n-heptane.

The product is obtained as an amorphous colorless solid

Mass Spectrometry (DCI): 33L (M + 1) < ⁺ > ^.

5b)

The diester of step 5a) is according to variant

1B is converted to diguanidide and converted to dihydrochloride. The melting point of the product is above 235 ° C

Mass spectrometry (DCI): 337 (M + 1)

Example 6

1- [3- (Ζ-2-fluoro-guanidide)] - 2- [3- (Ε-2-methyl-guanidide)] benzene dihydrochloride

6a) In the preparation of 7a), the isolated monoaldehyde monoester 6a) is also converted to the diester 6b) according to the procedure described in Example 4a).

Compound 6a) is a yellowish oil (chemical ionization, CI): 223 (M + 1) ⁺ ]

Compound 6b) is a yellowish oil [mass spectrometry (mass spectrometry (CI): 307 (M + 1) ⁺ J)

6c) According to variant 1B, the diester of step 6b) is converted to diguanidide and converted to the dihydrochloride. The melting point of the product is above 200 ° C.

Mass spectrometry (electrospray ionization, ES): 333 (M + 1) ⁺

Example 7

1,3-Bis [3- (Ζ-2-fluoro-guanidide) Ibenzén dihydrochloride

7a) Using a procedure known in the literature (Cousseau et al .: Tetrahedron Lett. 34, 6903 (1993)), starting from 1,3-isophthalialdehyde, benzene-1,3-di- [3- (Z-2-fluoropropene) diethyl ester is prepared. acid), which is purified and isolated on silica gel, eluting with a mixture of ethyl acetate and n-heptane. The product is obtained as an amorphous colorless solid

Mass Spectrometry (DCI): 331 (M + 1) < + >

7b) The diester of step 7a) is converted to diguanidide according to variant 1B and converted to the dihydrochloride. The product is obtained in the form of an orange-yellow colored solid with a melting point above 180 ° C.

Mass spectrometry (ES): 337 (M + 1) < + >

Example 8

3- (4-Chloro-3-guanidinocarbonyl-5-phenyl) phenyl-2-methylpropenuanide

nh ₂

8a) 3-Bromo-2-chloro-5-methylbenzoic acid g 2-Amino-3-bromo-5-methylbenzoic acid is dissolved in

500 ml of 6N aqueous hydrogen chloride solution, at 0 ° C, add 8.25 g of sodium nitrite and diazotize at this temperature for 30 minutes. This diazonium salt solution is then added dropwise to a solution of 22 g of copper (I) chloride in 200 ml of a saturated aqueous solution of hydrogen chloride at 40 ° C and the mixture is subsequently stirred at this temperature for 20 minutes. The product is filtered off with suction, washed with 500 ml of water and dried under gentle vacuum at 40 ° C. 23.3 g of white crystals with a melting point of 170172 ´C are obtained

Rf ₍ 5: 1 ethyl acetate / methanol): 0.51 Mass Spectrometry (DCI): 249 (M + H) < ^{+ >}

8b) 3'-Bromo-2-chloro-5-dibromomethylbenzoic acid g 3-Bromo-2-chloro-5-methylbenzoic acid is dissolved in 150 ml of chlorobenzene and the mixture is heated to reflux. At this temperature, 7.2 g of N-bromosuccinimide and 0.5 g of benzoyl peroxide are initially added and the mixture is refluxed for 30 minutes. Then 7.2 g of N-bromosuccinimide and 0.5 g of benzoyl peroxide are added again and the mixture is refluxed for a further 3 hours. After cooling, it is added

200 ml of ethyl acetate, washed with 50 ml of a saturated aqueous solution of sodium sulfite and 300 ml of a saturated aqueous solution of potassium dihydrogen phosphate, and the aqueous phase is extracted twice with 200 ml of ethyl acetate each time. The extract was dried over sodium sulfate and the solvent was removed in vacuo. 14.1 g of a yellow oil are obtained.

Rf (diisopropyl ether with 2% acetic acid): 0.32

8c) 3-Bromo-2-chloro-5-formylbenzoic acid

11.7 g of silver nitrate are dissolved in 150 ml of water and 150 ml of methanol and a solution of 14 g of 3-bromo-2-chloro-5-dibromomethylbenzoic acid in 100 ml of methanol is added dropwise. The mixture is stirred for 30 min at room temperature, 100 ml of saturated aqueous sodium chloride solution are added, the silver salt is filtered off with suction and the solvent is removed in vacuo. To the residue is added 200 ml of 5% aqueous potassium hydrogen sulphate solution and extracted three times with 200 ml of ethyl acetate each time. The extract was dried over sodium sulfate and the solvent was removed in vacuo. Chromatography on silica gel, eluting with diisopropyl ether with 2% acetic acid, afforded 3.6 g of colorless crystals, m.p. 148 ° C.

_Rf (DIP 2% HOAc) = 0.12

Mass spectrometry (DCI): 263 (M + H) < ⁺ > ^.

8d) 3-Bromo-2-chloro-5-formyl-benzoic acid ethyl ester

3.6 g of 3-bromo-2-chloro-5-formylbenzoic acid are dissolved in 100 ml of ethanol, 2.9 g of thionyl chloride are added dropwise, and the mixture is refluxed for 5 hours. The volatiles were then removed in vacuo and the residue chromatographed on silica gel, eluting with ethyl acetate / n-heptane (1: 8) to give 2.7 g of a colorless oil.

Rf ₍ 1: 8 ethyl acetate / n-heptane): 0.24 Mass Spectrometry (DCI): 291 (M + H) < ^{+ >}

8e) 3- (3-Bromo-4-chloro-5-ethoxycarbonyl) phenyl-2-methylpropenoic acid ethyl ester

2.7 g of 3-bromo-2-chloro-5-formylbenzoic acid ethyl ester was analogously to Example 4a) subjected to the Wittig-Horner reaction to give 3.4 g of a colorless oil.

Rf (1: 8 ethyl acetate / n-heptane): 0.27 Mass Spectrometry (DCI): 374 (M + H) < ^{+ >}

8f) 3- (4-Chloro-3-ethoxycarbonyl-5-phenyl) -phenyl-2-methyl-propenoic acid ethyl ester

3.3 g of 3- (3-bromo-4-chloro-5-ethoxycarbonyl) phenyl-2-methylpropenoic acid ethyl ester, 1.23 g of phenylboronic acid, 2.14 g of sodium carbonate, 576 mg of triphenylphosphine and 227 mg of acetate The palladium (II) is dissolved in 150 ml of toluene and 40 ml of water and the solution is refluxed for 7 hours. The mixture is cooled to room temperature and 200 ml of ethyl acetate are added, the mixture is washed twice with 100 ml of a saturated aqueous sodium carbonate solution and 100 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent is removed in vacuo. Chromatography on silica gel using ethyl acetate / nheptane (1: 8) as eluent gave 800 mg of a colorless oil.

Rf (1: 8 ethyl acetate: n-heptane): 0.25 DCI: 372 (M + H) < ^{+ >}

8g) 3- (4-chloro-3-guanidinocarbonyl-5-phenyl) phenyl-2-methylpropenuanide

Dissolve 1.8 g of potassium tert-butoxide in 100 ml of N, N-dimethylformamide, add 1.82 g of guanidine hydrochloride and stir at room temperature for 1 hour. 700 mg of 3- (4-chloro-3-ethoxycarbonyl-5-phenyl) phenyl-2-methylpropenoic acid ethyl ester are then added and the mixture is stirred for 5 hours at 100 ° C. The reaction mixture is poured into 200 ml of water and extracted three times 200 ml ethyl acetate. The extract was dried over sodium sulfate and the solvent was removed in vacuo. Chromatography on silica gel, eluting with acetone / water (10: 1) afforded 170 mg of an amorphous foam.

Rf ₍ 10: 1 acetone / water): 0.23 Mass Spectrometry (Fast Neutral Particle ionization, EAB) 399 (M + H) ⁺

Example 9

1,3-Bis [3- (Ε-2-methyl-guanidide)] - 2-methoxy-5-methyl-benzene hydrochloride

9a) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents of 2-methoxy-5-methyl-1,3-isophthalialdehyde is added at room temperature. After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. 2-Methoxy-5-methylbenzene-1,3-di- [3- (E-2-methylpropenoic acid) diethyl ester] was isolated as a colorless oil.

MS (CI): 347 (M + 1) < ^{+ >}

9b) The ester from step 9a) is saponified by a standard procedure using sodium hydroxide in methanol. 2-Methoxy-5-methylbenzene-1,3-di- [3- (E-2-methylpropenoic acid)] is isolated as a colorless solid, m.p. 196 ° C.

Mass Spectrometry (DCI): 295 (M-H) < tb >

9c) The dicarboxylic acid of step 9b) is converted to diguanidide according to variant 1A and isolated as the hydrochloride. The product is a colorless solid with a melting point of 279 ° C. Mass Spectrometry (NBA): 373 (M + 1) ⁺

Example 10

1,2-bis- [3- (E-2-methyl-propene-guanidide)] -4-methylbenzene dihydrochloride

10a, b) The 4-methylphthalic acid diester is converted to the dialcohol 10a by standard procedure (e.g. reduction with lithium aluminum hydride). Thereafter, this alcohol is oxidized to dialdehyde 10b) under standard conditions (e.g. by Swern oxidation).

dialcohol 10 a) is a colorless oil [mass spectrometry (DCI): 153 (M +) * and 135 (M + 1-H 2 O)]. dialdehyde 10b) is a dark oil [weight spectrometry

(CI): 149 (M + 1) +].

10c) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

4-methyl-1,2-phthalialdehyde 10b). After the dialdehyde had reacted completely, the mixture was treated with water and the organic phase was dried three times to dry the solvent. The solvent was removed in vacuo, and the diethyl ester was evaporated in vacuo and shaken with toluene over magnesium sulfate remaining crude on silica gel.

After the product is eluted

Isolate

4-methylbenzene-1,2-di- [3- (E-2-methylpropene acid acetate and n-heptane).

in the form of a colorless oil.

Mass spectrometry (CI): 317 (M + 1) * 10d) The ester from step 10c) was saponified according to a standard procedure using sodium hydroxide in methanol. 4-Methylbenzene-1,2-di- [3- (E-2-methylpropenoic acid)] is isolated as a colorless solid, m.p. 194-198 ° C.

Mass spectrometry (CI): 260 (M *) 10e) The dicarboxylic acid from step 10d) was converted to diguanide dihydrochloride according to variant 1Ά. The product is a colorless solid with a melting point of 190 ° C.

MS (ES): 342 (M + 1) < ^{+ >}

Example 11

1,2-Bis [3- (Ε-2-methyl-guanidide)] - 4,5-dichloro-benzene dihydrochloride

11a, b) The 4,5-dichlorophthalic acid diester is converted to the dialcohol 11a) by a standard procedure (e.g. reduction with lithium aluminum hydride). Thereafter, this alcohol is oxidized to dialdehyde 11b) under standard conditions (e.g. by Swern oxidation).

Dialcohol 11a) is a colorless solid with a melting point of 147 ° C (mass spectrometry (CI): 207 (M + 1) ⁺ ).

Dialdehyde 11b) is an amorphous solid (mass spectrometry (CI): 203 (M + 1) ⁺ J).

11c) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents of 4,5-dichloro-1,2-phthalialdehyde 11b) is added at room temperature. After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. 4,5-Di-chlorobenzene-1,2-di- [3- (E-2-methylpropenoic acid) diethyl ester] is isolated as a colorless solid, m.p. > 230 ° C.

Mass spectrometry (CI): 371 (M + 1) ⁺ 11d) The diester from step 11c) was converted to diguanidide dihydrochloride according to variant 1B. The product is a colorless solid with a melting point above 220 ° C.

Mass spectrometry (ES): 397 (M + 1) ’

Example 12

1,3-bis- [3- (E-propene-guanidide)] benzene dihydrochloride

12a) 1 equivalent of triethylphosphonoacetate is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

1,3-isophthalialdehyde. After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with a mixture of ethyl acetate and n-heptane. Benzene-1,3-di [3- (E-propenoic acid)] diethyl ester was isolated as a colorless oil.

MS (CI): 275 (M + 1) < ^{+ >}

12b) The ester from step 12a) is saponified according to a standard procedure using sodium hydroxide in methanol. Benzene-

1,3- di- [3- (E-propenoic acid)] as a colorless solid with a melting point above 200 C. C.

Mass Spectrometry (DCI): 217 (M-1) < + >.

12c) According to variant 1A, the dicarboxylic acid of step 12b) is converted to diguanidide dihydrochloride. The product is a colorless solid with a melting point of 296 ° C.

MS (ES): 301 (M + 1) < ^{+ >}

Example 13 1,2-Bis- [3- (E-2-methyl-propene-guanidide)] -4-bromobenzene dihydrochloride

13a, b) The 4-bromophthalic acid dimethyl ester is converted to the dialcohol 13a by standard procedure (e.g. reduction with lithium aluminum hydride). Then, the alcohol is oxidized to dialdehyde 13b) under standard conditions (e.g. Swern oxidation).

Dialcohol 13a) is a colorless oil (mass spectrometry (DCI): 217 (M + 1) ⁺ and 199 (M + 1-H ₂ O)).

Dialdehyde 11b) is an amorphous solid (mass spectrometry (Cl): 213 (M + 1) ⁺ J).

13c) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

4-bromo-1,2-phthalialdehyde 13b). After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. 4-Bromobenzene-1,2-di- [3- (E-2-methylpropenoic acid) diethyl ester] was isolated as a colorless oil.

Mass spectrometry (Cl): 381 (M + 1) ’

13d) The ester of step 13c) is saponified by a standard procedure using sodium hydroxide in methanol. 4-Bromobenzene-1,2-di- [3- (E-2-methylpropenoic acid)] is isolated as a colorless amorphous solid.

MS (FAB) 325 (M + 1) < ^{+ >}

13e) The dicarboxylic acid of step 13d) is converted to diguanide dihydrochloride according to variant 1A. The product is a colorless solid, mp 240 ° C.

MS (FAB) 407 (M + 1) < ^{+ >}

Example 14

1,2-bis- [3- (E-2-methylpropenunidide)] -4- (4-methoxyphenoxy) benzene dihydrochloride

14a) 4-Nitrophthalic acid dimethyl ester is reacted with sodium 4-methoxyphenoxide in Ν, Ν-dimethylformamide to give the dimethyl ester in an analogous manner to that described in the literature (J. Org. Chem. 42 (21), 3419-3425 (1977)). 4- (4-methoxyphenoxy) phthalic acid. After standard work-up and chromatography, eluting with hexane / ethyl acetate, the diester is isolated as a brownish oil.

MS (Cl) 316 (M < ^{+ >} ), 317 (M + l < ^{+ >} )

14b, c) The diester 14a) is converted to dialcohol 14b) by a standard procedure (e.g. reduction with lithium aluminum hydride). Then, this alcohol under standard conditions (for example

Swern oxidation) oxidizes to dialdehyde 14c).

Dialcohol 14b) is a tan oil (mass spectrometry (Cl): 260 (M +)).

Dialdehyde 11b) is a brownish oil (mass spectrometry (Cl): 257 (M + 1) ⁺ J).

14d) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

1,2-phthalialdehyde 14c). After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. 4- (4-Methoxyphenoxy) benzene-1,2-di- [3- (E-2-methylpropenoic acid) diethyl ester] was isolated as a slightly brownish oil.

Mass Spectrometry (NBA): 424 (M @ +)

14e) The diester of step 14d) is saponified according to a standard procedure using sodium hydroxide in methanol. 4- (4-Methoxyphenoxy) benzene-1,2-di- [3- (E-2-methylpropenoic acid)] was isolated as a pale yellow solid, mp 112 ° C.

Mass spectrometry (ES): 368 (M < ^{+ >} )

14f) The dicarboxylic acid of step 14e) is converted to diguanidide dihydrochloride according to variant 1A. The product is a colorless solid with a melting point of 212 ° C.

MS (ES): 451 (M + 1) < ^{+ >}

Example 15

1 _t 2-Bis- [3- (E-2-methyl-propene-guanidide)] -4- (4-methyl-phenoxy) -benzene dihydrochloride

15a) 4-Nitrophthalic acid dimethyl ester with an analogous procedure to that described in the literature (J. Org. Chem. 42 (21),

3419-3425 (1977)) is reacted with sodium 4-methylphenoxide in Ν, Ν-dimethylformamide to give 4- (4-methylphenoxy) phthalic acid dimethyl ester. After standard work-up and chromatography, eluting with hexane / ethyl acetate, the diester is isolated as a yellowish oil.

Mass Spec (CI) 301 (M + 1 ⁺ )

15b, c) The diester 15a) is converted to dialcohol 15b) by a standard procedure (e.g. reduction with lithium aluminum hydride). Thereafter, this alcohol is oxidized to dialdehyde 15c) under standard conditions (e.g. by Swern oxidation).

Dialcohol 15b) is a yellowish oil (mass spectrometry (CI): 244 (M ⁺ ), 245 () + Γ)).

Dialdehyde 15c) is a brownish oil (mass spectrometry (CI): 241 (M + 1 ⁺ )).

15d) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

1,2-phthalialdehyde 15c). After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. 4- (4-Methylphenoxy) benzene-1,2-di- [3- (E-2-methylpropenoic acid) diethyl ester] was isolated as a slightly brownish oil.

Mass Spectrometry (NBA): 408 (W), 409 (M + 1 *)

15e) The diester of step 15d) is saponified using a standard procedure using sodium hydroxide in methanol. 4- (4-Methylphenoxy) benzene-1,2-di- [3- (E-2-methylpropenoic acid)] was isolated as a colorless solid, m.p. 185 [deg.] C. *)

15f) The dicarboxylic acid of step 15e) is converted to diguanidide dihydrochloride according to variant 1A. Colorless solid, mp 186 ° C.

MS (ES): 435 (M + 1) < ^{+ >}

Example 16

1,3-bis- [3- (E-2-methyl-preneguanidide)] - 5-methoxybenzene hydrochloride

16a) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

5-methoxy-3-isophthalaldehyde. After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. 5-Methoxybenzene-1,2-di- [3- (E-2-methylpropenoic acid) diethyl ester] was isolated as a colorless oil.

MS (Cl): 333 (M + 1 < ^{+ >} )

16b) The diester of step 16a) is saponified by a standard procedure using sodium hydroxide in methanol. 5-Methoxybenzene-1,3-di- [3- (E-2-methylpropenoic acid)] was isolated as a colorless solid, m.p. > 200 ° C.

Mass Spectrometry (DCI): 276 (M < ^{+ >} )

16c) The dicarboxylic acid of step 16b) is converted to diguanidide according to variant 1A and isolated as the hydrochloride. The product is a colorless solid, m.p. 124 [deg.] C. Mass Spectrometry (NBA): 359 (M + 1) < ^{+ >}

Example 17

1,3-bis- [3- (E-2-methyl-propene-guanidide)] - 5-tert-butyl-benzene hydrochloride

17a) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

5-tert-butyl-3-isophthalaldehyde. After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. 5-tert-Butylbenzene-1,3-di- [3- (E-2-methylpropenoic acid) diethyl ester] was isolated as a colorless oil.

MS (CI): 359 (M + 1 < ^{+ >} )

17b) The diester of step 17a) is saponified according to a standard procedure using sodium hydroxide in methanol. 5-tert-Butylbenzene-1,3-di- [3- (E-2-methylpropenoic acid)] is isolated as a colorless solid, m.p. > 200 ° C. Mass Spectrometry (DCI): 302 (M ⁺ )

17c) The dicarboxylic acid of step 17b) is converted to diguanidide according to variant 1A and isolated as the hydrochloride. The product is a colorless solid with a melting point of 115 ° C. Mass Spectrometry (NBA): 385 (M + 1) ^T

Example 18

1,4-bis- [3- (E-2-methyl-propene-guanidide)] - 2,5-dichlorobenzene dihydrochloride

CI

18a) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of butyl lithium in hexane and then 0.5 equivalents of 2,5-dichloro-1,4-terephthalialdehyde is added at room temperature. After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. 2,5-Dichlorobenzene-1,4-di- [3- (E-2-methylpropenoic acid) diethyl ester] is isolated as a colorless amorphous solid.

MS (Cl): 371 (M + 1 < ^{+ >} )

18b) The diester of step 18a) is saponified according to a standard procedure using sodium hydroxide in methanol. 2,5-Dichlorobenzene-1,4-di- [3- (E-2-methyl-propenoic acid)] is isolated as a colorless solid.

Mass Spectrometry (DCI): 315 (M < ^{+ >} )

18c) The dicarboxylic acid of step 18b) is converted to diguanidide dihydrochloride according to variant 1A. The product is a yellow solid with a melting point above 200 ° C.

MS (DCI) 397 (M + 1) < ^{+ >}

Example 19

1,2-Bis- [3- (E-2-methyl-propene-guanidide)] -4- (phenoxy) benzene dihydro chloride

19a) 4-Nitrophthalic acid dimethyl ester is reacted with sodium phenoxide in N, N-dimethylformamide to give 4-phenoxyphthalic acid dimethyl ester in an analogous manner to that described in the literature (J. Org. Chem. 42 (21), 3419-3425 (1977)). . After standard work-up and chromatography, eluting with hexane / ethyl acetate, the diester is isolated as a yellowish oil.

spectrometry (CI) 287 (M + 1 < ^{+ >} )

The diester 19a) is converted to dialcohol 19b) by standard procedure (e.g. lithium aluminum hydride). this alcohol under standard conditions (e.g.

wEIGHT

19b, c) reduction

Swern oxidation) oxidizes to dialdehyde 19c).

dialcohol 19b) is a yellowish oil. Mass spectrometry (CI): 230 (M < ^{+ >} ), 231 (Μ + Γ ) · dialdehyde 19c) is a brownish oil. Mass spectrometry

(CI): 227 (M + 1 < ^{+ >} )

19d) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

1,2-phthalialdehyde 19c). After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. 4- (Phenoxy) benzene-1,2-di- [3- (E-2-methylpropenoic acid) diethyl ester] is isolated as a slightly brownish oil.

Mass Spectrometry (NBA): 394 (M < ^{+ >} ), 395 (M + l < ^{+ >} )

19e) The diester of step 19d) is saponified using a standard procedure using sodium hydroxide in methanol. 4 (Phenoxy) benzene-1,2-di- [3- (E-2-methyl-propenoic acid)] is isolated as a colorless solid, m.p. 160 ° C.

MS (NBA): 338 (M ^T)

19f) The dicarboxylic acid of step 19e) is converted according to variant 1A to diguanidide dihydrochloride. The product is a colorless solid with a melting point of 170 ° C.

Mass spectrometry (ES): 421 (M + 1) '·

Example 20

1,2-Bis- [3- (E-2-methyl-propene-guanidide)] - 4 (methoxy) benzene dihydrochloride

The compound of Example 20 was prepared analogously to Example 19 by nucleophilic aromatic substitution of the 4-nitrophthalic acid ester with sodium methoxide, followed by reduction, oxidation, olefination reaction, saponification and guanidation of the dicarboxylic acid.

Compound 20a) is 4-methoxyphthalic acid diester (mass spectrometry (CI): 225 (M + 1 ⁺ )).

Dialcohol 20b) (CI): 169 (M + 1 ⁺ )].

is a tan oil [mass spectrometry

Compound 20e) Propenoic acid)], is a dark oil dark oil [mass [mass spectrometry spectrometry

4- (methoxy) benzene-1,2-di- [3- (EN-2-methyl) as a solid which is obtained with a melting point above 200 ° C. (NBA): 27 6 (M ⁺ ) ].

20f) According to variant 1A, the dicarboxylic acid of step 20e) is converted to diguanidide dihydrochloride. The product is a colorless solid with a melting point of 170 ° C.

Mass spectrometry (ES): 359 (M + 1) < ^{+ >}

Example 21

1,2-Bis- [3- (E-2-methylpropenuanidide)] -4- (ethoxy) benzene dihydrochloride

(21a) 4-Ethoxyphthalic acid diethyl ester is prepared by ethylating 4-hydroxyphthalic acid with 3,5-equivalents of ethyl iodide and 3.1 equivalents of potassium carbonate in N, N-dimethylformamide at 70 ° C. which, according to variant 1B, is converted to diguanidide 21e).

Compound 21a) is 4-ethoxyphthalic acid diethyl ester, which is obtained as a brown oil (mass spectrometry (CI): 267 (M + 1 ⁺ )).

Dialcohol 21b) is a tan oil (mass spectrometry (CI) 183 ((+ Γ)).

Dialdehyde 21c) is a dark oil (mass spectrometry (CI): 179 (M + 1 ⁺ )).

Diester 21d) is a yellowish oil (mass spectrometry (NBA): 347 (M + 1 ⁺ )).

21e) According to variant 1B, the diester 21d) is converted to diguanide dihydrochloride. Colorless solid, m.p. 245 ° C.

MS (ES): 373 (M + 1) ^r

Example 22

1,2-Bis- [3- (E-2-methyl-propene-guanidide)] -4- (3-pyridyloxy) -benzene dihydrochloride

22a) 4-Nitrophthalic acid dimethyl ester is reacted with 3-hydroxypyridine sodium salt in Ν, Ν-dimethylformamide in an analogous manner to that described in the literature (J. Org. Chem. 42 (21), 3419-3425 (1977)) to give of dimethyl 4- (3-pyridyloxy) phthalic acid dimethyl ester. After standard work-up and chromatography, eluting with hexane / ethyl acetate, the diester was isolated as a yellowish oil.

MS: 288 (M + 1 < + >)

22b, c) The diester 22a) is converted to dialcohol 22b) by a standard procedure (e.g. reduction with lithium aluminum hydride). Then this alcohol is oxidized to dialdehyde 22c) under standard conditions (e.g. Swern oxidation).

Dialcohol 22b) is a yellowish oil [MS: 232 (M + 1 < ^{+ >} )].

Dialdehyde 22c) is a tan oil [MS: 228 (M + 1 < ^{+ >} )].

22d) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

1,2-phthalialdehyde 22c). After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. 4- (3-Pyridyloxy) benzene-1,2-di- [3- (E-2-methylpropenoic acid) diethyl ester J is isolated as a slightly brownish oil.

MS: 396 (M + 1 < + >)

22e) The diester of step 22d) is saponified according to a standard procedure using sodium hydroxide in methanol. 4- (3-pyridyloxy) benzene-1,2-di- [3- (E-2-methyl-propenoic acid) is isolated as a colorless solid, m.p. 210 DEG C. Mass spectrometry: 339 (MH @ ⁺ )

22f) The dicarboxylic acid of step 22e) is converted to diguanidide dihydrochloride according to variant 1A. The product is a colorless solid with a melting point of 176 ° C.

Mass Spectrometry: 422 (M + 1) *

Example 23

1,2-bis- [3- (E-2-methylpropenuanidide)] - 4- [4- (2-dimethylaminoethylene) phenoxy] benzene dihydrochloride

23a) 4-Nitrophthalic acid dimethyl ester is reacted in analogous manner to that described in the literature (J. Org. Chem. 42 (21), 3419-3425 (1977)) with 4- (2-dimethylaminoethylene) phenol sodium salt in Ν, Ν-dimethylformamide to give 4- [4- (2-dimethylamino-ethylene) -phenoxy] -phthalic acid dimethyl ester. After standard work-up and chromatography, eluting with hexane / ethyl acetate, the diester is isolated.

Mass Spectrometry: 358 (M + 1 ”)

23b, c) The diester 23a) is converted to dialcohol 23b) by standard procedure (reduction with lithium aluminum hydride). Thereafter, this alcohol is oxidized to dialdehyde 23c) by the Dess-Martin reaction (see Dess-Martin Oxidation, J. Org. Chem. 59, 7549-7552 (1994)).

Dialcohol 23b) is a tan oil (mass spectrometry: 340 (M + 1 ⁺ )).

Dialdehyde 23c) is a yellow oil, [Mass Spectrometry: 269 (M + 1 ⁺ )].

23d) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

1,2-phthalialdehyde 23c). After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. 4- [4- (2-Dimethylaminoethylene) phenoxy] benzene-1,2-bis- [3- (E-2-methylpropenoic acid) diethyl ester] was isolated as a yellowish oil.

MS: 466 (M + 1 < ^{+ >} )

23e) The diester of step 23d) is saponified according to a standard procedure using sodium hydroxide in methanol. 4- [4- (2-Dimethylaminoethylene) phenoxy] benzene-1,2-bis- [3- (E-2-methylpropenoic acid)] is isolated as a colorless solid, m.p. > 220 ° C.

Mass Spectrometry: 409 (M ')

23f) The dicarboxylic acid of step 23e) is converted to diguanidide dihydrochloride according to variant 1A.

Mass Spectrometry: 410 (M + 1) *

Examples 24 and 25

1,2-bis- [3- (E-2-methyl-propene-guanidide)] - 4- (4-methoxybenzyloxy) benzene dihydrochloride and 1,2-bis- [3- (E-2-methyl-propene-guanidide)] 4-hydroxybenzene dihydrochloride

24a) 1 equivalent of 4-hydroxyphthalic acid dimethyl ester, 1.1 equivalent of potassium carbonate and 1.1 equivalent of 4-methoxybenzyl chloride are stirred at room temperature in N, N-dimethylformamide. After 4 days, the reaction mixture was worked up by standard procedures. 4- (4-Methoxybenzyloxy) phthalic acid dimethyl ester was isolated as a colorless oil. Mass Spectrometry: 331 (M + 1 ⁺ )

24b, c) The diester 24a) is converted to dialcohol 24b) by a standard procedure (reduction with lithium aluminum hydride). Thereafter, this alcohol is oxidized to dialdehyde 24c) under standard conditions (e.g., Swern oxidation).

Dialcohol 24b) is an amorphous solid [mass spectrometry: 275 (M + 1 ⁺ )].

Dialdehyde 24c) is a yellowish oil [mass spectrometry: 271 (Μ + Γ)].

24d) 1 equivalent of 2-phosphonopropionic acid triethyl ester is deprotonated at 0 ° C with one equivalent of n-butyllithium in hexane and then 0.5 equivalents are added at room temperature

1,2-phthalialdehyde 24c). After the dialdehyde had completely reacted, the mixture was treated with water and shaken three times with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the remaining crude product is chromatographed on silica gel, eluting with ethyl acetate / n-heptane. 4- [4-Methoxybenzyloxy] benzene-1,2-bis- [3- (E-2-methylpropenoic acid) diethyl ester] was isolated as a yellowish oil.

MS: 439 (M + 1 < ^{+ >} )

24e) The diester of step 24d) is saponified according to a standard procedure using sodium hydroxide in methanol. 4- [4-Methoxybenzyloxy] benzene-1,2-bis- [3- (E-2-methylpropenoic acid) is isolated as a colorless solid, m.p. 206-220 ° C.

MS: 382 (M < ^{+ >} )

24f) The dicarboxylic acid of step 24e) is converted to diguanidide dihydrochloride according to variant 1A. Melting point 210 ° C.

MS: 465 (M + 1) < ^{+ >}

Example 25

1,2-bis- [3- (E-2-methyl-propene-guanidide)] - 4-hydroxybenzene dihydrochloride

The dicarboxylic acid of step 24e is converted to diguanidide dihydrochloride according to variant 1A. In addition to the compound of Example 24, the product 25 is isolated. Mass Spectrometry: 345 (M + 1) *

Pharmacological data:

Inhibition of Na ⁺ / H ⁺ exchange system (subtype 1; NHE-1) in rabbit erythrocytes

The white New Zealand rabbits (Ivanovas) receive a standard diet with 2% cholesterol for six weeks to activate Na * / H * exchange and thereby gain the ability to determine Na ⁺ influx into erythrocytes by Na ⁺ / H ⁺ exchange by flame photometry. Blood is drawn from the ear artery and prevented from clotting with 25 IU / ml potassium heparin. A portion of each sample is used for duplicate determination of hematocrit by centrifugation. Parts with a volume of 100 μΐ each serve to measure the original Na * content of erythrocytes.

To determine the sodium influx sensitive to amiloride, 100 μΐ of each blood sample is incubated in 5 ml of hyperosmolar saline sucrose medium (140 mmol / L sodium chloride, 3 mmol / l potassium chloride, 150 mmol (1 sucrose, 0.1 mmol / l) each. ouabaine, 20 mmol / l trishydroxymethylaminomethane) at pH 7.4 and 37 ° C. The erythrocytes are then washed three times with an ice-cold solution of magnesium chloride and ouabine (112 mmol / l magnesium chloride, 0.1 mmol / l ouabine) and hemolyzed. in 2.0 ml of distilled water The intracellular sodium content is determined by flame photometry.

The net Na ⁺ influx is calculated from the difference between the initial sodium content and the sodium content of the erythrocytes after incubation. Amiloride-inhibiting sodium influx is obtained from the difference in sodium contents in erythrocytes after incubation in the presence and absence of amiloride in an amount of 3 x 10 ^-4 mol / l. The same applies to the compounds of the invention.

Results of inhibition of Na ⁺ / H ⁺ exchange system (subtype 1; NHE-1):

Example compound IC ₅₀ (mol 4 4

Most procedures in molecular biology are performed using protocols from Current Protocols in Molecular Biology (Ausbel FM, Brent R., Kingston RE, Moore DD, Seidman JG, Smith JA and Struhl K. Eds.), John Wiley & Cloning: A Laboratory Manual (Sambrock J., Fritsch EF and Mantias T. Eds.), Cold Spring Harbor Laboratory Press (1989). In the investigations carried out, stable transfected cell lines have been established which express the following NHE subtypes: human NHE-1 (Sardet et al., Cell 56, 271-280 (1989)), rabbit NHE-2 (Tse et al .: J. Biol. Chem., 268, 11917-11924 (1993)), or rat NHE-3 (Orlowski et al., J. Biol. Chem. 267, 9331-9339 (1992)).

cDNA clones of individual NHE subtypes, supplied by prof. Pouyssegur, cloned into the pMAMneo expression plasmid (available from, for example, CLONTECH, Heidelberg), after appropriate linker sequences have been joined, such that the plasmid sequence recognizing NHE-1 lies approximately 20-100 base pairs in front of the start codon of the NHE subtype and the entire coding sequence present.

Using the so-called calcium phosphate method (described in chapter 9.1 of Current Protocols in Molecular Biology), NHE-free LAP-1 cell lines (Franchi et al., Proc. Natl. Acad. Sci. USA 83, 9388-9392 (1986)) were transfected with plasmids. into which said coding sequences of NHE subtypes have been introduced. After selection of the transfected cells by growing them in medium containing G 418 (under these conditions, only cells that have been transfected with a neogen) can be selected for functional expression of NHE. The acid load technique described by Sardet was used (Sardet et al., Cell 56, 271-280, (1989)). Cells that express functional NHE subtypes can, even in the absence of carbon dioxide and bicarbonate anions, compensate for acidification performed in this assay, which untransfected LAP-1 cells cannot. After repeated selection of the acidic selection, the surviving cells were plated on the microtiter plates so that one cell per well should be statistically output. After approximately 10 days, the microscope examined how many colonies were growing in each well. Cell populations from single cell colonies were then screened with the XTTProliferation Kit (Boehringer, Mannheim) for their ability to survive acidic stress. The best cell lines were used for further assays, and to prevent loss by transfection of the introduced sequence, these cell lines were cultured under constant selection pressure in media containing G 418.

To determine IC50 values, a specific test developed by S. Faber (Faber et al .: Cell. Physiol. Biochem. 6, 39-49 (1961)) for the inhibition of individual NHE subtypes by specific agents was modestly based on an acidic technique. load.

This assay reveals the return of intracellular pH (pHi) to the original values after acidification, which in the presence of NHE capable of functioning also occurs in a non-bicarbonate environment. For this purpose, pHi is determined using a pH sensitive fluorescent dye, BCEF (Calbiochem, precursor used).

BCECF-AM). BCECF is first introduced into the cells.

The BCECF fluorescence is determined by a spectrometer

Ratio

fluorescence

Spectrometer ”(Photon

Technology International, South Brunswick, N.J., 505 and 440 nm excitation wavelengths and emitted wavelengths

USA) at 535 nm and converted to ρΗ _± using calibration curves. In contrast to the described protocol, cells are already incubated in NH ₄ Cl buffer (pH 7.4) when BCECF is introduced. The composition of NH ₄ Cl-buffer is as follows: 115 mM sodium chloride, 20 mM ammonium chloride, 5 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium sulfate, 20 mM Hepes (4- (2-hydroxyethyl) -1-piperazinethanesulfonic acid) ), 5 mM glucose and 1 mg / ml BSA (bovine serum albumin), the pH being adjusted to 7.4 with 1M sodium hydroxide. Intracellular acidification is induced by adding 975 μ75 of ammonium chloride-free buffer to the cell samples incubated in 25 μΐ NH ₄ Cl buffer. The following pH recovery rates found for NHE-1 are 2 minutes, for NHE-2 5 minutes and for NHE-3 3 minutes. To calculate the inhibitory potency of the test substances, the cells are first examined in buffers in which complete or no return of pH to the original values occurs. To completely return the pH to 100%, cells are incubated in a buffer containing sodium cations (buffer composition: 133.8 mM sodium chloride, 4.7 mM potassium chloride, 1.25 mM calcium chloride, 1.25 mM magnesium chloride, 0.97 mM sodium phosphate dibasic, 0.23 mM sodium phosphate dibasic, 5 mM Hepes (4- (2-hydroxyethyl) -1-piperazinethanesulfonic acid, and 5 mM glucose, pH adjusted to 7.0 with 1M sodium hydroxide) For the determination of 0%, the cells are incubated in a buffer free of sodium cations (buffer composition: 133.8 mM choline chloride, 4.7 mM potassium chloride, 1.25 mM calcium chloride, 1.25 mM magnesium chloride, 0.97 mM potassium hydrogen phosphate, 0.23 mM potassium dihydrogen phosphate, 5 mM Hepes (4- (2-hydroxyethyl) -1-piperazinanesulfonic acid) and 5 mM glucose, pH adjusted to 7.0 with 1M sodium hydroxide. to be tested, they are applied in a buffer containing The return of intracellular pH to the original values for each test concentration of the substance is expressed as a percentage of the maximum return of the pH to the original values. From these percentages of pH recovery, SigmaPlot calculates IC50 values for a given NHE subtype.

Example compound IC50 for NHE-3 1 0.7 6 3.2 9 1.75 3 1.1

Claims (20)

PATENT CLAIMS A phenylsubstituted alkenyl carboxylic acid guanidide of the general formula I in which T represents a group of the general formula R ^f is H, F, Cl, Br, I, CN, OH, OR ^6, C 1 -C 4 alkyl, O _b (CH ₂₎ * CBF _{2 b} »i, cycloalkyl having 3 to 8 carbon atoms or NR ⁷ R ⁸ , r is 0 or 1, and is 0, 1, 2, 3, or 4, b is 1, 2, 3, or 4 R ⁶ is C 1 -C 4 alkyl, C 1 -C 4 perfluoroalkyl, C 3 -C 6 alkenyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, the phenyl ring being unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁹ R ¹⁰ groups, R ⁹ and R ¹⁰ are each hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 perfluoroalkyl, R ⁷ and R ⁸ are each independently as defined for R ⁶ , or R ⁷ and R ⁸ together represent 4 or 5 methylene groups, of which one CH ₂ may be replaced by an oxygen, sulfur, NH, N-CH ₃ or N-benzyl group, R ^B , R ^C and R ^D are each independently the meaning defined for R ^A , x is 0, 1 or 2, y is 0, 1 or 2, R ^F is H, F, Cl, Br, I, CN, OR ^12, alkyl of 1 to 8 carbon atoms, O _{p (CH2)} fC _{g of} F _{2 g +} i, cycloalkyl having 3 to 8 carbon atoms or a heteroaryl group having 1 to 9 carbon atoms, P my value 0 or b F my value 0, 1, 2 3 or 4, g my value 1, 2, 3 4, 5, 6, Ί or 8 R ¹² is C 1 -C 8 alkyl, C 1 -C 4 perfluoroalkyl, C 3 -C 8 alkenyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, the phenyl ring being unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ¹³ R ¹⁴ groups, R ¹³ and R ¹⁴ are each hydrogen, alkyl of 1 to 4 carbon atoms or C 1 -C 4 perfluoroalkyl, R ^e is independently as defined for R ^F , R ¹ is independently as defined for the symbol T, or R ¹ represents H, -OkCmH2m + i, -0n (CH2) i-pCqF2q, F, Cl, Br, I, CN, - (C = O) -N = C (NH 2) 2, -S0rR ^17, -SOr2NR ³¹ R ^32, _in -0 (CH ₂₎ C ₆ H _{5 /} -0 group _{U2-heteroaryl} having 1 to 9 carbon atoms or s 2 _U-heteroaryl having 1 to 9 carbon atoms, to my 0 or 1 m my 0, 1, 2, 3, 4, 5, 6, 7, or 8 n my 0 or 1 P my 0, 1, 2, 3, or 4 q my 1, 2, 3, 4, 5, 6, 7, or 8 r my 0, 1, or 2 r2 my 0, 1, or 2 symbols R ³¹ and R ³² are each independently atom hydrogen, C 1 -C 8 alkyl or C 1 -C 8 perfluoroalkyl, or R ³¹ and R ³² together represent 4 or 5 methylene groups, of which one CH ₂ may be replaced by an oxygen, sulfur, NH, N-CH ₃ or N-benzyl, R ¹⁷ is C 1 -C 8 alkyl, u is 0 or 1, u 2 is 0 or 1 v is 0, 1, 2, 3 or 4, wherein the phenyl ring is unsubstituted or substituted with one to three substituents selected a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, - (CH ₂ ) _W NR ²¹ R ²² , NR ^1B R ¹⁹ and heteroaryl groups of 1 to 9 carbon atoms, R ¹⁸ , R ¹⁹ , R ²¹ and R ²² are each C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl, w is 1, 2, 3 or 4 wherein the heterocycle of the C 1 -C 9 heteroaryl group is unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl and methoxy, R ² , R ³ , R ⁴ and R ⁵ are independently much of one another the meanings defined for R ^1, or the radicals R ¹ and R ² or R ² and R ³ each stand for a -CH-CH-CH-CH-, which is unsubstituted or substituted with one to three substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, - (CH ₂ ) _{W 2} NR ²⁴ R ²⁵ and NR ²⁶ R ²⁷ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁷ are each hydrogen, alkyl C1-C4 or C1-C4 perfluoroalkyl, and w2 is 1, 2, 3 or 4, wherein the T moiety is present in the molecule at least twice but at most three times as well as their pharmaceutically acceptable salts. The phenyl substituted alkenylcarboxylic acid guanidides of the formula I according to claim 1, wherein T represents a group of the formula R ^a represents a hydrogen, fluorine or chlorine atom, cyano, hydroxy, OR ⁶ , alkyl 1 to C 4 -C 6 cycloalkyl 0 _{R (CH2)} aCbF2b.l / atoms or NR ⁷ R ^8, 3 to 8 group atoms r my value 0 or 1 and my value 0, 1, or 2, b my value 1, 2, 3 or 4 R ⁶ atoms represents an alkyl group having 1 to perfluoroalkyl having 1 to phenyl or benzyl, the phenyl ring being unsubstituted substituted by one to three substituents selected from carbon, carbon, or fluorine, chlorine, trifluoromethyl, methyl , methoxy and NR ⁹ R ^10; R ⁹ and R ¹⁰ independently of one another, are hydrogen, methyl or trifluoromethyl; R ⁷ and R ⁸ independently of one another each as defined for the symbol R ^6, or symbols R ⁷ and R ⁸ together represent 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen, sulfur, NH, N-CH ₃ or N-benzyl group, R ®, R ^c and R ^d are independently always has the meaning defined for R ^A , x is 0 or 1, y is 0 or 1, R ^f represents a hydrogen, fluorine or chlorine atom, a cyano group, an OR ¹² group, a C 1 -C 4 alkyl group, a 0 _p (CH ₂ ) fCgF ₂ g + 1 group, a C 3 -C 3 cycloalkyl group Or C 1 -C 8 heteroaryl 9 carbon atoms, p is 0 or 1, f is 0, 1 or 2 g is 1, 2, 3 or 4, R ¹² is C 1 -C 4 alkyl, C 1 -C 4 perfluoroalkyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, wherein the phenyl ring is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 -C 4 alkyl; consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy and NR ¹³ R ^14; R ¹³ and R ¹⁴ independently of one another, are hydrogen, methyl or trifluoromethyl, R ^e is independently as defined for R ^F , R ¹ is independently as defined for the symbol T, or R ¹ represents H, -OkCmH2m + i, i + -OnCqF2q, F, Cl, Br, I, CN, - (C = O) -N = C (NH 2) 2, -SOR ^17, -SOr2NR ³¹ R ^32, -O _u (CH ₂₎ C ₆ H _5, -O _u2 heteroaryl of 1-9 carbon atoms, or -S _u2 heteroaryl having 1 to 9 carbon atoms, k is 0 or 1, m is 0, 1, 2, 3 or 4 n is 0 or 1 q is 1, 2, 3 or 4 r is 2, r 2 is 0, 1 or 2, R ³¹ and R ³² are each independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl, or R ³¹ and R ³² together represent 4 or 5 methylene groups, of which one may be one CH ₂ replaced by oxygen, sulfur, NH, N-CH ₃ or N-benzyl, R ¹⁷ is C 1 -C 4 alkyl, u is 0 or 1, u 2 is 0 or 1 v is 0, 1 or 2 wherein the phenyl ring is unsubstituted or substituted with one to three substituents selected from fluoro , chloro, trifluoromethyl, methyl, methoxy, - (CH _{2) w} NR ²¹ R ^22, NR ^{X 8} R ^19, and heteroaryl of 1-9 carbon atoms; R ^18, R ^19, R ²¹ and R ²² each represents a hydrogen atom, a (C1-C4) alkyl group or a (C1-C4) perfluoroalkyl group, w has a value of 1, 2, 3 or 4, wherein the heterocycle of the (C 1 -C 9) heteroaryl group is unsubstituted or substituted by one to three substituents selected from the group consisting of F, Cl, trifluoromethyl, methyl and methoxy radicals R ^2, R ^3, R ⁴ and R ⁵ independently of one another in the Always as defined for R ^1, or the radicals R ¹ and R ² or R ² and R ³ each stand for a -CH-CH-CH-CH-, unsubstituted or substituted with one to three substituents selected from the group consisting of F, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, - (CH ₂ ) _W 2 NR ²⁴ R ²⁵ and NR ²⁶ R ²⁷ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁷ are each hydrogen, methyl or trifluoromethyl and w 2 has a value of 1, 2, 3 or 4, however, the residue T in the molecule is present only twice. A compound of the formula I as claimed in claim 1 or 2, in which T represents a group of the formula x is 0, y is 0, r ^f represents a hydrogen, fluorine or chlorine atom, CN, OR ^12, alkyl of 1 to 4 carbon atoms, O _p C _g F _{2 < +} 1, C 3 -C 8 cycloalkyl or C 1 -C 9 heteroaryl, p is 0 or 1, g is 1, 2, 3 or 4 . R ¹² is C 1 -C 4 alkyl, trifluoromethyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, the phenyl ring being in each case unsubstituted or substituted by one to three substituents selected from fluorine, chloro, trifluoromethyl, methyl, methoxy and NR ¹³ R ^14; R ¹³ and R ¹⁴ are hydrogen, methyl or trifluoromethyl, R ^e is independently as defined for R ^F , R ¹ is independently as defined for the symbol T, or R ¹ represents a hydrogen atom, a group -O _to C _m H _{2m +} 1, -O _n CqF _{2q +} 1, a fluorine or chlorine atom, a cyano group, a - (C = O) -N = C (NH ₂ ) _{2 group} , -SO ₂ CH ₃ - SO ₂ NR ³¹ R ³² , -0 _u (CH ₂ ) _in C ₆ H ₅ , group -O _u2 -heteroaryl s 1 until 9 carbon atoms or -S _u2 -heteroaryl of 1 to 9 carbon alkyl, to my value 0 or 1 m my value 0, 1, 2, 3 or 4 n my value 0 or 1 q my value 1, 2, 3 or 4 symbols R ³¹ and R ³² independently of each other himself means in each case a hydrogen atom or alkyl having 1 to 4 carbon atoms, or R ³¹ and R ³² together represent 4 or 5 methylene groups of which one CH ₂ group may be replaced by an oxygen, sulfur, NH, N-CH ₃ or N-benzyl group u is 0 or 1, u2 is 0 or 1 v is 0 or 1 wherein the phenyl ring is unsubstituted or substituted by one to three including an atom, methyl - (CH ₂ ) _W NR ²¹ R ²² and NR ¹⁰ R ¹⁹ , substituents selected from fluorine, chlorine, trifluoromethyl, methoxy, R ¹⁸ , R ¹⁹ , R ²¹ and R ^{22 are} each independently hydrogen , (C 1 -C 4) alkyl or (C 1 -C 4) perfluoroalkyl, w having a value of 1, 2, 3 or 4, wherein the heterocycle of the C 1 -C 9 heteroaryl group is unsubstituted or substituted by one to three substituents selected from the group including fluorine, chlorine, trifluoromethyl, methyl and methoxy, R ² , R ³ , R ⁴ and R ⁵ are each independently as defined for R ¹ , or R ¹ and R ² or R ² and R 5 ³ together represent in each case a -CH-CH = CH-CH- group which is unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group; UPIN methyl, methoxy, - (CH ₂₎ w2NR ²⁴ R ²⁵ and NR ²⁶ R ^27; R ^24, R ^25, R ²⁶ and R ²⁷ independently of one another are hydrogen, alkyl having 1 to 4 carbon or a C 1 -C 4 perfluoroalkyl group and w 2 is 1, 2, 3 or 4, with the remainder T being present only twice in the molecule. A compound of the formula I as claimed in one or more of claims 1 to 3, selected from the group consisting of: 1,2-bis- [3- (E-2-methyl-propene-guanidide)] benzene dihydrochloride, 1,3-bis- [3- (E-2-methyl-propene-guanidide)] benzene dihydrochloride, 1,4-Bis [3- (Ε-2-methyl-guanidide)] benzene dihydrochloride, 2,3-bis- [3- (E-2-methyl-propene-guanidide)] naphthalene dihydrochloride, 1,2-bis- [3- (Ζ-2-fluoro-propene-guanidide)] benzene dihydrochloride, 1- [3- (Ζ-2-fluoro-guanidide)] - 2- [3- (Ε-2-metylpropénguanidid) Jbenzén dihydrochloride, 1,3-bis- [3- (Ζ-2-fluoro-propene-guanidide)] benzene dihydrochloride, 3- (4-chloro-3-guanidinocarbonyl-5-phenyl) phenyl-2-methyl-guanidide 1,3-Bis- [3- (E-2-methyl-propene-guanidide)] - 2-methoxy-5-methylbenzene hydrochloride 1,2-Bis- [3- (E-2-methyl-propene-guanidide)] -4-methylbenzene dihydrochloride 1,2-Bis- [3- (E-2-methyl-propene-guanidide)] - 4,5-dichlorobenzene dihydrochloride 1,3-bis- [3- (E-propene-guanidide)] benzene dihydrochloride 1,2-Bis- [3- (E-2-methyl-propene-guanidide)] - 4-bromobenzene dihydrochloride 1,2-Bis- [3- (E-2-methylpropenuanidide)] - 4- (4-methoxyphenoxy) benzene dihydrochloride 1,2-Bis- [3- (E-2-methyl-propene-guanidide)] - 4- (4-methyl-phenoxy) -benzene dihydrochloride 1,3-bis- [3- (E-2-methyl-propene-guanidide)] - 5-methoxybenzene hydrochloride 1,3-bis- [3- (E-2-methyl-propene-guanidide)] - 5-tert-butyl-benzene hydrochloride 1,4-bis- [3- (E-2-methyl-propene-guanidide)] 2,5-dichlorobenzene dihydrochloride 1,2-Bis- [3- (E-2-methyl-propene-guanidide)] - 4- (phenoxy) benzene dihydrochloride 1,2-Bis- [3- (E-2-methyl-propene-guanidide)] 4- (methoxy) benzene dihydrochloride 1,2-bis- [3- (E-2-methyl-propene-guanidide)] - 4- (ethoxy) benzene dihydrochloride and 1,2-Bis- [3- (E-2-methyl-propene-guanidide)] - 4- (3-pyridyloxy) -benzene dihydrochloride. A process for the preparation of a phenylsubstituted alkenylcarboxylic acid guanidide of the formula I according to claim 1, characterized in that the compound of the formula II x wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^A , R ^B , R ^c , R ^c , R ^E _Z R ^F , x and y have the meanings given above and L is a nucleophilic substitution readily substitutable leaving group , is reacted with guanidine. Use of a phenylsubstituted alkenylcarboxylic acid guanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment of arrhythmias. 7. A compound according to claim 1 for use in the treatment of arrhythmias. Use of a phenylsubstituted alkenylcarboxylic acid guanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of a heart attack. Use of a phenylsubstituted alkenylcarboxylic acid guanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of angina pectoris. Use of a phenyl-substituted alkenylcarboxylic acid guanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of ischemic heart conditions. Use of a phenyl-substituted alkenylcarboxylic acid guanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and stroke. Use of a phenylsubstituted alkenylcarboxylic acid guanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs. Use of a phenyl-substituted alkenylcarboxylic acid guanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment of shock conditions. Use of a phenylsubstituted alkenylcarboxylic acid guanidide of the formula I according to claim 1 for the manufacture of a medicament for use in surgical operations and organ transplants. Use of a phenylsubstituted alkenylcarboxylic acid guanidide of the formula I according to claim 1 for the manufacture of a medicament for the preservation and storage of transplants for surgical procedures. Use of a phenylsubstituted alkenylcarboxylic acid guanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment of diseases whose primary or secondary cause is cellular proliferation. Use of a phenylsubstituted alkenylcarboxylic acid guanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of disorders of fat metabolism. Use of a phenylsubstituted alkenylcarboxylic acid guanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of disorders associated with impaired respiratory stimulation. Use of a phenylsubstituted alkenylcarboxylic acid guanidide of the formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of acute and chronic renal diseases, in particular acute renal failure and chronic renal failure. The amount of acid of the claims A medicament comprising an effective phenyl-substituted alkenylcarboxylic guanidide of the formula I according to one or more of 4 to 4.